Aminoacid Based Chiral N-Amidothioureas. Acetate Anion ... · Aminoacid Based Chiral...

Aminoacid Based Chiral N-Amidothioureas. Acetate Anion

Binding Induced Chirality Transfer

Fang Wang,a Wen-Bin He,a Jin-He Wang,a Xiao-Sheng Yan,a Ying Zhan,a Ying-Ying

Ma,b Li-Cai Ye,a Rui Yang,b Fu Cai,a Zhao Li a and Yun-Bao Jiang*,a

a. Department of Chemistry, College of Chemistry and Chemical Engineering, and the

MOE Key Laboratory of Analytical Sciences, Xiamen University, Xiamen 361005,

China. Tel: +86 592 218 8372; Fax: +86 592 218 5662;

E-mail: [email protected]

b. College of Chemistry and Chemical Engineering, Southwest University, Chongqing

400715, China

Electronic Supplementary Information (ESI)

Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2011

NH2

OH

O

SOCl2 , CH3OH

Reflux, 80oCNH2

OCH3

O

HCHO, NaBH4

THF, rt

N

OCH3

O

N2H4 H2O, EtOH

Reflux, 80oCN

NHNH2

ONCS

CH2Cl2, rt

N

N

O

N N

S

HH

H

1

2 3

L / D-PLTU

L / D-phenylalanine

Scheme S1. Syntheses of L-/D-PLTU, L-BPTU and L-PATU


Methyl 2-amino-3-phenylpropanoate (1): 21.5 ml (295.0 mmol) SOCl2 was added dropwise to

9.7 g (58.8 mmol) L-phenylalanine in 300 ml methanol at -30 ◦C. After warming up to room

temperature, the mixture was refluxed for 2 h. The organic solvent was removed at reduced

pressure, and the pH of the residue was adjusted to ca. 9 using NH3·H2O. The mixture was then

extracted by Et2O for three times (3x15 ml). The combined organic layer was washed with little

brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure, to obtain 10.0 g 1,

95%.

N,N-Dimethylphenylalanine methyl ester (2): A solution of 1.0 g (5.6 mmol) (S)-(+)-1 in 56 ml

THF and solid NaBH4 1.477 g (39.1 mmol) were slowly added (simultaneously) to a solution of

6.0 ml 37% formaldehyde (208 mmol) and 5.6 ml 20% H2SO4 in 28 ml THF over a period of 15

min at room temperature. The reaction mixture was stirred for additional 15 min and then the pH

was adjusted to 9 using diluted aqueous KOH. The resulting suspension was extracted by ethyl

acetate (3x15 ml) and the combined organic layer was washed with brine and dried with

anhydrous Na2SO4. The crude product was purified using column chromatography on silica gel

column eluted with petroleum ether and ethyl acetate (10:1, v/v) to give the

N,N-dimethylphenylalanine methyl ester 2 as yellowish oil, 754 mg (65%).

2-(Dimethylamino)-3-phenylpropanehydrazide (3): Aqueous hydrazine (80%) was added to 2

in ethanol (5.0 ml) and then refluxed for 24 hours. A viscous liquid was obtained after removing

solvent under reduced pressure, which was subject to chromatography on a silica gel column

eluted with CH2Cl2/CH3OH (20:1, v/v) to afford 3, 621 mg (83%).

2-(2-(Dimethylamino)-3-phenylpropanoyl)-N-phenylhydrazinecarbothioamide (L-/D-PLTU):

3 then reacted with phenyl isothiocyanate in CH2Cl2. The solution was stirred at room temperature

for 12 hours, after which the solvent was removed under reduced pressure. The product was

purified by chromatography on a silica gel column eluted with CH2Cl2/CH3OH (40:1, v/v).

L-PLTU: 1H NMR (400MHz, DMSO-d6): (ppm), 10.01 (s, 1H), 9.73 (s, 1H), 8.88 (s, 1H), 7.42 (s,

2H), 7.34 (t, 2H, J = 8.0 Hz), 7.21-7.27 (m, 4H), 7.13-7.18 (m, 2H), 3.47 (t, 1H, J = 6.0 Hz),

2.98-3.03 (m, 1H), 2.85-2.90 (m, 1H), 2.32 (s, 1H); 13C NMR (100MHz, CDCl3): (ppm), 178.0,

168.5, 138.5, 137.4, 129.1, 128.6, 126.6, 126.3 124.6, 69.7, 42.3, 32.7; HRMS (ESI): calcd for

[C9H9F3N3OS+]: 343.1593, found: 343.1591. D-PLTU: 1H NMR (400MHz, DMSO-d6): (ppm),

10.01 (s, 1H), 9.70 (s, 1H), 8.83 (s, 1H), 7.41 (s, 2H), 7.32 (t, 2H, J = 8.0 Hz), 7.21-7.26 (m, 4H),

7.12-7.17 (m, 2H), 3.45 (t, 1H, J = 6.0 Hz), 2.97-3.01 (m, 1H), 2.84-2.89 (m, 1H), 2.31 (s, 1H);

13C NMR (100MHz, CDCl3): (ppm), 178.0, 168.4, 138.5, 137.5, 129.1, 128.6, 126.6, 126.2 124.5,

69.7, 42.3, 32.7; HRMS (ESI): calcd for [C9H9F3N3OS+]: 343.1593, found: 343.1579.

1-Ethoxy-1-oxo-3-phenylpropan-2-aminium chloride (4): To a 50 ml round-bottom flask


equipped with magnetic stirring were added 1.65 g (10 mmol) L-phenylalanine and 25 ml of

ethanol. The solution was stirred in an ice bath for 10 min, sulfuryl dichloride 2 ml was added

dropwise. The reaction mixture stirred for 0.5 h at room temperature, and then was heated at reflux

for 3 h. The solvent was removed and the crude product was purified to afford pure 4 (0.198 g,

65% yield).

Ethyl 2-benzamido-3-phenylpropanoate (5): To a 25 ml round-bottom flask equipped with

magnetic stirring were added 0.12 g (1 mmol) benzoic acid and 15 ml of dichloromethane. The

solution was stirred in an ice bath for 10 min, sulfuryl dichloride 0.5 ml was added dropwise. The

reaction mixture stirred for 0.5 h at room temperature, and then was heated at reflux for 3 h. The

solvent was removed to give a white solid residue (benzoyl chloride).

0.25 g (1.5 mmol) of 4, 1 ml triethylamine and 25 ml of dichloromethane were added to a 50 ml

round-bottom flask equipped with magnetic stirring. Benzoyl dichloride in 5 ml dichloromethane

was added dropwise. The reaction mixture stirred in an ice bath for 0.5 h and then stirred at room

temperature for another 4 h. The solvent was removed and the crude product was washed with

dilute sodium carbonate solution and diethylether for several times to afford crude product 5 (0.23

g, 77% yield).

2-Benzamido-3-phenylpropanehydrazide (6): 0.23 g of 5, 2 ml hydrazine hydrate (80%) and 20

ml of ethanol was added to a 50 ml round-bottom flask equipped with magnetic stirring. The

reaction mixture was heated at reflux for 5 h. The solvent was removed, and the crude product was

washed with diethylether several times to afford crude product 6 (0.2 g, 90% yield).

1-(2-Benzamido-3-phenylpropanoyl)-4-phenylthiosemicarbazide (L-BPTU): 0.2 g of 3, 0.5 ml

1-isothiocyanatobenzene and 20 ml of ethanol was added to a 50 ml round-bottom flask equipped

with magnetic stirring. The reaction mixture was stirred for 12 h. The solvent was removed, and

the crude product was washed with ether several times to afford pure L-BPTU (0.24 g, 80% yield).

1H NMR (500 MHz, DMSO-d6, TMS): δ=10.45 (s, 1H), 9.78 (s, 1H), 9.25 (s,1H), 8.89 (s,1H),

7.79 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 6.6 Hz, 2H), 7.53 (t, J = 7.0 Hz, 1H), 7.45 (t, J = 7.3 Hz, 2H),

7.35 (t, J = 7.0 Hz, 4H), 7.28 (t, J = 7.3 Hz, 2H), 7.18 (m, J = 13.7, 7.0 Hz, 2H), 4.59 (s, 1H), 3.21

(s, 1H), 3.15 – 3.07 (m, 1H). 13C NMR (500 MHz, DMSO-d6, TMS): δ 180.26, 170.73, 167.35,

138.93, 137.78, 133.44, 131.50, 129.11, 128.13, 128.11, 127.41, 126.28, 124.77, 124.21, 54.50,

36.01. HRMS (ESI): calcd for C23H22O2N4S m/z 419.1536 [M+H+]; found 419.1530 [M+H+].

(L)-Methyl 2-phenylpropanoate (7): To a mixture of 0.15 g (1.0 mmol) (R)-2-phenylpropanonic

acid in 10 ml of methanol was added dropwise SOCl2 0.5 ml at -30 ◦C. After warming up to room

temperature, the reaction mixture was heated to 70 ◦C for 8 h. The organic solvent was

concentrated under reduced pressure and the residue was washed with water. The mixture was


extracted three times with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and

concentrated under reduced pressure, to obtain 0.16g 7, 95%.

(L)-2-Phenylpropanehydrazide (8): Aqueous hydrazine (80%) was added to 7 in ethanol (5.0 ml)

and then refluxed for 24 hours. After removing solvent under reduced pressure, white solide was

obtained which was purified on a silica gel column eluted with CH2Cl2/CH3OH (60:1, v/v) to

afford 8, 0.12g (80% yield).

(L)-N-Phenyl-2-(2-phenylpropanoyl)hydrazinecarbothioamide (L-PATU): 8 then reacted with

phenyl isothiocyanate in CH2Cl2. The solution was stirred at room temperature for 12 hours, after

which the solvent was removed under reduced pressure. The product was purified by

chromatography on a silica gel column eluted with CH2Cl2/CH3OH (80:1, v/v). 1H NMR

(400MHz, CD3CN): (ppm), 8.46 (s, 1H), 8.38 (s, 1H), 7.92 (s, 1H), 7.43 (s, 1H), 7.40 (t, 4H, J =

4.0 Hz), 7.35-7.39 (m, 3H), 7.29-7.33 (m, 1H), 7.25 (t, 1H, J = 8.0 Hz), 3.72-3.78 (m, 1H), 1.50 (d,

3H, J = 4.0 Hz); 13C NMR (100MHz, CD3CN: (ppm), 182.3, 174.0, 141.1, 138.3, 128.7, 128.5,

127.6, 127.4, 127.2, 126.0, 125.3, 117.4, 44.3, 17.9.

-5

0

5

200 240 280 320 360 4000.0

0.4

0.8

,

mde

g

Wavelength, nm

296 nm

(b)

Abs

orba

nce

[AcO] / [D-PLTU]

0

2.5(a)

Figure S1. Absorption (a) and CD (b) spectra of D-PLTU in acetonitrile in the presence of acetate

anion. [D-PLTU] = 40 μM.


240 320 400 4800.0

0.1

0.2

0.3

0.4

0.5

NN

-O2CCO2

-

NN

-O2C

-O2C

trans-ADA cis-ADA

Abs

orb

ance

Wavelength, nm

445 nm

(a)

(b)

340 nm

Figure S2. Absorption spectra of trans- (a) and cis-ADA (b) in acetonitrile. [ADA] = 20 M.

-5

0

5

-5

0

5

200 250 300 350 400 450 5000.0

0.5

1.0

1.5

,

mde

g

Wavelength, nm

296 nm

(b)

(c)

Abs

440 nm

[ADA], M

0

50(a)296 nm

Figure S3. Absorption (a) and CD (b, c) spectra of PLTU in acetonitrile in the presence of

cis-ADA. L- (a, b) and D-PLTU (c). [PLTU] = 40 M, [ADA] = 0-50 M.


Figure S4. NMR traces of L-PLTU in CD3CN in the presence of acetate anion. [L-PLTU] = 10

mM.

Figure S5. Splitting of NMR signals of gemini protons Ha and Hb next to chiral α-carbon centre in

L-PLTU in the presence of acetate of increasing concentration in CD3CN. [PLTU] = 10 mM. For

numbering of protons Ha and Hb see Scheme 2 in the main text.


Scheme S2. X3LYP/6-311++G(d,p)-optimized structure of PLTU with Me2N...HNC(O)

five-membered ring intramolecular hydrogen bond. Hydrogen bond length: N(22)…H(14), 2.27 Å;

ond angle: N(22)-H(14)-N(2): 100.26o ; Dihedral angle: N(22)-H(14)-N(2)-C(1): -10.78o .

Figure S6. Portion of NMR traces of L-PLTU in DMSO-d6/CD3CN binary solvents of increasing

volume fraction of DMSO-d6. Pink and green peaks are signals of thioureido -NH protons and the

red one is that of the N-amido -NH proton.


Figure S7. 1H-1H COSY spectrum of BPTU in CD3CN. [BPTU] = 10 mM. Crossing peaks

highlighted by red circles allow the assignment of the signals to the indicated protons.

Figure S8. 1H-1H NOESY spectrum of BPTU in CD3CN. Coupling of signals of NH1 and phenyl

CH6 shown in the bold red circle is a support of the seven-membered intramolecular hydrogen

bond between -NH1 and benzamido C=O.


Figure S9. Portion of 1H NMR spectra of L-BPTU in CD3CN-DMSO-d6 binary solvents. [BPTU]

= 10 mM. The reluctant response of the -NH1 signal (red peak) towards the solvent composition

suggests its involving in an intramolecular hydrogen bond.

0.0

0.4

0.8

1.2

1.6

200 240 280 320 360 400

-8

-4

0

4

Abs

(a)

(b)

CD

/ m

deg

Wavelength, nm

Figure S10. Absorption (a) and CD (b) spectra of L-BPTU in acetonitrile in the presence of AcO.

[BPTU] = 40 M; [AcO] = 0 to 200 M.


-10

-5

0

5

10

200 240 280 320 360 4000.0

0.3

0.6

0.9

1.2

,

mde

g

Wavelength, nm

265 nm (b)

Abs

orba

nce [AcO, M

0

15

(a)

296 nm

Figure S11 Absorption (a) and CD (b) spectra of L-PATU in acetonitrile in the presence of acetate

anion. [L-PATU] = 40 μM.

1H NMR and 13C NMR spectra of L-/D-PLTU, L-BPTU and L-PATU

1H NMR of L-PLTU (400 MHz, DMSO-d6)


13C NMR of L-PLTU (100 MHz, CDCl3)

1H NMR of D-PLTU (400 MHz, DMSO-d6)


13C NMR of D-PLTU (100 MHz, CDCl3)

1H NMR of L-BPTU (500 MHz, DMSO-d6)


13C NMR of L-BPTU (125 MHz, DMSO-d6)

1H NMR of L-PATU (400 MHz, CD3CN)


13C NMR of L-PATU (100 MHz, CD3CN)


Aminoacid Based Chiral N-Amidothioureas. Acetate Anion ... · Aminoacid Based Chiral...

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